Szmuszkovicz U.S. Pat. No. 4,145,435 discloses some cis- and trans-N-(2-aminocycloaliphatic)-2-arylacetamide derivative compounds, e.g., N-[2-(N',N'-dimethylamino)cyclohexyl]-N-methyl-2-(4-bromophenyl)-ace tamide and trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-2-(3,4-dichlorophenyl)acet amide, which have potent analgesic activity; the preferred compounds thereof have, in addition, only low to moderate apparent physical dependence liability compared to morphine and methadone.
Also, Szmuszkovicz U.S. Pat. No. 4,098,904 discloses some cis- and trans-N-(2-aminocycloaliphatic)benzamide compounds, e.g., N-methyl-N-(2-aminocycloaliphatic)benzamide compounds, e.g., N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-3,4-dichlorobenzamide, which have potent analgesic activity, making them useful for relieving pain in warm-blooded animals.
Lednicer U.S. Pat. No. 4,212,878 discloses some N-[(1-amino-4-(mono- or di-oxygen-group-substituted)cyclohexyl)methyl]benzeneacetamide derivatives, e.g., 2-(3,4-dichlorophenyl)-N-[[8-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8-yl] methyl]acetamide, which also have analgesic drug properties with lower physical dependence liability characteristics than morphine or methadone. That Lednicer patent also refers to what is now Lednicer U.S. Pat. No. 4,065,573 which discloses some 4-amino-4-phenylcyclo hexanone keta compounds, e.g., 4-(m-hydroxyphenyl)-4-(dimethylamino)cyclohexanone ethylene ketal and 4-(m-hydroxyphenyl)-4-(n-butylmethylamino)cyclohexanone ethylene ketal, which are useful for relieving pain in animals, some of which compounds exhibit narcotic antagonist activity.
More recently, in the above identified cross-referenced application, we described and claimed some new 2-aminocycloaliphatic-benzeneacetamide and -benzamide compounds bearing oxy- or thia-group substituents on a cycloaliphatic ring carbon not adjacent to the nitrogen bearing carbons of that cycloaliphatic ring, e.g., trans-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8 -yl]-benzeneacetamide, and salts thereof, which were found to have useful ranges of analgesic properties while also having low apparent physical dependence liability properties. Those compounds were described by the general formula (I): ##STR1## wherein p and n are each full number integers of from 1 to 3, so that the resulting cycloaliphatic ring has five to seven carbon atoms; the wavy line bond (.about.) between the nitrogen in the 2-position and the cycloaliphatic ring carbon indicates the bond can be either cis- or trans- with respect to each substituent of the cycloaliphatic ring;
q is 0 or 1; PA0 X and Y are independently selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl, nitro, methoxy, hydroxy, azido, C.sub.1 to C.sub.3 -alkyl, phenyl, methanesulfonyl, cyano, amino, C.sub.1 to C.sub.3 -alkoxycarbonyl, C.sub.1 to C.sub.3 -alkanoyloxy, C.sub.1 to C.sub.3 -carboxyacylamino [(-NHC(O)R.sub.6)]; PA0 R is hydrogen or C.sub.1 to C.sub.3 -alkyl; PA0 R.sub.1 and R.sub.2, taken separately, are hydrogen, C.sub.1 to C.sub.3 -alkyl, allyl, or PA0 R.sub.1 and R.sub.2, taken together with the nitrogen to which they are bonded, complete a ring selected from the group consisting of azetidinyl, pyrrolidinyl and piperidinyl; PA0 R.sub.3, taken separately, is hydrogen, hydroxy, --OR.sub.5 or OC(.dbd.O)R.sub.6 ; PA0 R.sub.4, taken separately, is hydrogen; PA0 R.sub.3 and R.sub.4, taken together, are selected from the group consisting of PA0 --ECH.sub.2 CH.sub.2 E--, PA0 .dbd.E, PA0 .dbd.N.about.OH, and PA0 .dbd.N.about.OC(O)CH.sub.3, PA0 wherein each E is bivalent sulfur or oxygen, and R.sub.3 and R.sub.4 cannot both by hydrogen at the same time; PA0 R.sub.5 is C.sub.1 to C.sub.3 -alkyl; PA0 R.sub.6 is H, or C.sub.1 to C.sub.2 -alkyl; and the acid addition salts thereof, particularly pharmaceutically acceptable salts thereof. PA0 q is 0 or 1; PA0 X and Y are independently selected from the group consisting of hydrogen, a halogen having an atomic number of from 9 to 35, trifluoromethyl, nitro, methoxy, hydroxy, azido, C.sub.1 to C.sub.3 -alkyl, phenyl, methanesulfonyl, cyano, amino, C.sub.1 to C.sub.3 -alkoxycarbonyl, C.sub.1 to C.sub.3 -alkanoyloxy, C.sub.1 to C.sub.3 -carboxacylamino [(--NHC(O)R.sub.6)]; PA0 R is hydrogen or C.sub.1 to C.sub.3 -alkyl; PA0 R.sub.1 and R.sub.2, taken separately, are hydrogen, C.sub.1 to C.sub.3 -alkyl, allyl, or PA0 R.sub.1 and R.sub.2, taken together with the nitrogen to which they are bonded, complete a ring selected from the group consisting of azetidinyl, pyrrolidinyl and piperidinyl; PA0 R.sub.3, taken separately, is hydrogen, and PA0 R.sub.4, taken separately, is mercapto (SH), --S--(C.sub.1 to C.sub.3 -alkyl), or R.sub.3 is --GR.sub.5 and R.sub.4 is --GR.sub.5 ; PA0 wherein E is bivalent sulfur or oxygen; PA0 each G is bivalent sulfur or oxygen; PA0 R.sub.5 is C.sub.1 to C.sub.2 -alkyl; PA0 R.sub.6 is H or C.sub.1 to C.sub.2 -alkyl; PA0 and the acid addition salts thereof, particularly pharmaceutically acceptable salts thereof. Thus, the R.sub.3, R.sub.4 -substituent moiety is in the 4-position of cyclopentyl ring compounds, in the 4- or 5-position of cyclohexyl ring compounds (or a mixture of compounds wherein the R.sub.3 and R.sub.4 substituents are on the 4- and 5-positions), and in the 4-, 5- or 6-positions of cycloheptyl ring compounds (or a mixture of such R.sub.3, R.sub.4 position isomers). Thus, this invention involves compounds wherein the R.sub.3, R.sub.4 -bearing carbon is not vicinal (adjacent) to either of the nitrogen bearing carbons of that same cycloaliphatic ring. PA0 R is C.sub.1 to C.sub.3 -alkyl; PA0 R.sub.1 and R.sub.2 are taken together with the nitrogen to which they are bonded to complete an azetidinyl, pyrrolidinyl or piperidinyl ring; PA0 R.sub.3 and R.sub.4 are each a --GR.sub.5 group, R.sub.5 is C.sub.1 to C.sub.2 -alkyl and G is oxygen, and E is oxygen, and the pharmaceutically acceptable salts thereof. Examples of compounds of this group include the cis- and trans-isomers of: PA0 3,4-dichloro-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzene acetamide which can also be named: PA0 3,4-dichloro-N-methyl-N-[4-oxo-2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamid e, dimethyl ketal, PA0 3,4-dichloro-N-[5,5-diethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzenea cetamide, PA0 4-bromo-N-[4,4-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzamide, PA0 3,4-dichloro-N-[4,4-dimethoxy-2-(1-azetidinyl)cyclopentyl]-N-ethylbenzeneac etamide, PA0 3,4-difluoro-N-[4,4-dimethoxy-2-(1-piperidinyl)cycloheptyl]-N-methylbenzene acetamide, PA0 4-bromo-N-[6,6-diethoxy-2-(1-pyrrolidinyl)cycloheptyl]benzamide, and the like, and the pharmacologically acceptable salts thereof.
The above general Formula I compounds, particularly at the R.sub.3 and R.sub.4 substituent definitions, do not include the compounds of this invention.